Combination antiretroviral therapy employing inhibitors of constitutive viral enzymes reverse transcriptase and protease, have resulted in dramatic clinical and virologic responses. As treated analyses of trials employing multi-drug regimens has documented reductions of plasma HIV-1 RNA below the level of detection of the most sensitive HIV-1 RNA assays in as many as 70 to 90% of subjects after two years of therapy. Nevertheless, the issue of ongoing replication does remain. Based on the biphasic decay of plasma HIV RNA after initiation of combination antiretroviral therapy, it has been hypothesized that complete suppression of virus replication for two or three years could effectively allow for all previously infected cells to decay, allowing for drug discontinuation. Three groups have recently shown that replication competent virus remains in latently infected resting CD4 cells, thereby raising significant doubts to the two to three year time frame. Our efforts to understand the decay of this compartment by measuring proviral DNA as a surrogate has uncovered interesting data. There appears to be differential rates of proviral DNA decay in subjects treated with combination antiviral therapy. Some patient show rather dramatic decreased in levels of proviral DNA over time whereas other individuals show no decay. One interpretation is that we are observing differential degrees of suppression of virus replication. That is, those with no decay or slow decay are replenishing the pool via ongoing virus replication, whereas those with more rapid decreases in levels of proviral DNA are pharmacologically "suppressed" to a greater degree. Further evidence of ongoing replication has been derived from sequences derived from proviral DNA of a subject treated with ZDV/3TC/Ritonavir within 90 days of infection. Despite persistently undetectable HIV-1 RNA levels, longitudinal sequencing of proviral DNA in the region of the envelope (C2 to V5) indicates genetic variation. In order to generate such variation over time, there must be virus replication, albeit at a very low level. Finally, we have used semi-quantitative PCR to assess levels of multiply-spliced and unspliced mRNA in the peripheral blood of patients on combination regimens. We can detect significant levels of unspliced mRNA in the PBMC of the majority of individuals with suppressed plasma viremia treated for 1 to 2 years with combinations of ZDV/3TC and either nelfinavir or ritonavir/saquinavir. The presence of US-mRNA suggests that low levels of virus replication may be occurring. Intensive sequencing efforts of pol from the proviral DNA or culturable virus from patient PBMC has not revealed the presence of resistance-associated mutations. Therefore, we are left with evidence of virus replication in the presence of drug, yet without selecting for drug resistance. It would seem that ongoing replication is occurring in areas where drug is unable to both suppress replication and as well exert a selective effect. The most satisfactory explanation is one of "compartmentalization" of virus producing cells from drug effect. Whether this is anatomic or pharmacologic cannot be determined, however, it would appear that one solution to this problem is to intensify the regimen with drugs with potency and favorable pharmacologic profiles. Therefore, we propose to add efavirenz and abacavir, both potent, well tolerated, and user friendly antiviral agents to the already existing regimens which include ZDV/3TC in combination with either retonavir, indinavir, nelfinavir, or ritonavir/saquinavir. In light of the known drug-drug interactions of efavirenz with protease inhibitors, doses of protease inhibitors will be adjusted accordingly.